Cabergoline is an ergoline derivative with formula 1 ((6-allylergolin-8β-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea. It is known for treatment of a number of diseases, including CNS disorders, reversible obstructive airways disease, prolactin inhibition, for controlling intra-ocular pressure and for treating glaucoma.
A number of different forms of cabergoline are known and, by way of example, PCT patent publication no. WO 01/72747 describes cabergoline Form II and PCT patent publication no. WO 01/72746 describes cabergoline Form VII.
Preparation of cabergoline Form I is described in PCT patent publication nos. WO 01/70740, WO 03/078392 and WO 03/078433. PCT patent publication no. WO 01/70740 teaches the preparation of crystalline Form I cabergoline from a solvent comprising a toluene/diethylether mixture whereas PCT patent publication nos. WO 03/078392 and WO 03/078433 teach crystalline cabergoline Form I that is obtained by drying a solvate of cabergoline and toluene.
Pending UK Patent Application No. GB 0409785-3 teaches a process for preparing cabergoline Form 1 in high yield and purity and with desirable particle size distribution using ethylbenzene optionally in conjunction with an antisolvent such as n-heptane. GB 0409785-3 further describes a cabergoline ethylbenzene solvate.
A series of cabergoline polymorphs are described in PCT patent publication no. WO 2004/101510.
It is desired in the present invention to prepare crystalline cabergoline of Form I having high purity. It is also desired to prepare cabergoline having a particle size (following crystallization) which is relatively small and which requires no or relatively little milling to obtain the particle size desired in the eventual pharmaceutical product. Milling and other such processing is undesirable as it tends to lead to conversion of pure polymorphic forms of cabergoline into polymorphic mixtures. One problem with the methods described. in PCT patent publication no. WO 03/078433, for example, is that crystals of cabergoline Form I are obtained with a relatively large particle size.
It is also desired to provide a process for preparation of cabergoline in which conversion of an intermediate solvate to the final cabergoline Form I product is quick and efficient. A difficulty with known processes for this conversion is that protracted drying periods are required to remove the solvent from the solvate—in excess of 48 hours—for the methods set forth in PCT patent publication no. WO 03/078433.